US5880126A - 9H-Pyridu ((3,4-b) indole derivatives - Google Patents
9H-Pyridu ((3,4-b) indole derivatives Download PDFInfo
- Publication number
- US5880126A US5880126A US08/875,090 US87509097A US5880126A US 5880126 A US5880126 A US 5880126A US 87509097 A US87509097 A US 87509097A US 5880126 A US5880126 A US 5880126A
- Authority
- US
- United States
- Prior art keywords
- group
- pyrido
- indole
- carboxylic acid
- benzyloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical class C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- -1 indole compound Chemical class 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001272 (C1-C4)-alkylene-phenyl group Chemical group 0.000 claims description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 125000000477 aza group Chemical group 0.000 claims description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 101150108015 STR6 gene Proteins 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 150000002475 indoles Chemical class 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 6
- 230000003042 antagnostic effect Effects 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 abstract description 2
- VNYSSYRCGWBHLG-AMOLWHMGSA-M leukotriene B4(1-) Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC([O-])=O VNYSSYRCGWBHLG-AMOLWHMGSA-M 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 201000010099 disease Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 12
- 150000002617 leukotrienes Chemical class 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- GYLYBMJFTWUCEB-UHFFFAOYSA-N 2-bromo-n-methyl-n-(2-phenylethyl)acetamide Chemical compound BrCC(=O)N(C)CCC1=CC=CC=C1 GYLYBMJFTWUCEB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 206010009887 colitis Diseases 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 210000001835 viscera Anatomy 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 210000000663 muscle cell Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 230000008728 vascular permeability Effects 0.000 description 2
- PYSODLWHFWCFLV-MVZIKBKVSA-N (5s,6r,7e,9e,11z,14z)-6-[(2r)-2-[[(4r)-4-amino-4-carboxybutanoyl]amino]-2-carboxyethyl]sulfanyl-5-hydroxyicosa-7,9,11,14-tetraenoic acid Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(O)=O)NC(=O)CC[C@@H](N)C(O)=O PYSODLWHFWCFLV-MVZIKBKVSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006824 (C1-C6) dialkyl amine group Chemical group 0.000 description 1
- OCSZBAHPQSTCNP-UHFFFAOYSA-N 1-(6-bromohexyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCCCCCBr)C=C1 OCSZBAHPQSTCNP-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JEIQZYJYZNLUIL-UHFFFAOYSA-N 2-bromo-n-phenyl-2-piperazin-1-ylacetamide Chemical compound C=1C=CC=CC=1NC(=O)C(Br)N1CCNCC1 JEIQZYJYZNLUIL-UHFFFAOYSA-N 0.000 description 1
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 description 1
- XMZQWZJMTBCUFT-UHFFFAOYSA-N 3-bromopropylbenzene Chemical compound BrCCCC1=CC=CC=C1 XMZQWZJMTBCUFT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229910003556 H2 SO4 Inorganic materials 0.000 description 1
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 description 1
- 206010064000 Lichenoid keratosis Diseases 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910004809 Na2 SO4 Inorganic materials 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 208000008350 Pruritus Vulvae Diseases 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010056530 Vulvovaginal pruritus Diseases 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 230000007646 directional migration Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000037189 immune system physiology Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000005550 inflammation mediator Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- OTZRAYGBFWZKMX-JUDRUQEKSA-N leukotriene E4 Chemical compound CCCCCC=CCC=C\C=C\C=C\[C@@H](SC[C@H](N)C(O)=O)[C@@H](O)CCCC(O)=O OTZRAYGBFWZKMX-JUDRUQEKSA-N 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- PPHQUIPUBYPZLD-UHFFFAOYSA-N n-ethyl-n-methylaniline Chemical compound CCN(C)C1=CC=CC=C1 PPHQUIPUBYPZLD-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- R 1 represents a hydrogen atom, a hydroxy group or a carboxyl group
- R 2 symbolizes a hydrogen atom, a hydroxy group, a C 1 -C 4 alkoxy group, a C 1 -C 6 alkanoyloxy group or a C 1 -C 4 - ⁇ -carboxyalkoxy group, or
- R 1 and R 2 together are an oxycarbonyl group, and in which
- X means a carbon-carbon bond or an oxygen
- Y means a carbon-carbon bond, the grouping --CONR' with R' in the meaning of a hydrogen atom or a C 1 -C 7 alkyl group that is optionally substituted by a carboxyl group, or the grouping ##STR2## with m and n in the meaning of numbers of a total of 3, 4 or 5, and Z in the meaning of a methylidine group or an aza group, and
- R 3 and R 4 in each case symbolize a phenyl group optionally substituted by halogen atoms, trifluoromethyl groups, cyanide groups, C 1 -C 7 alkyl groups, C 1 -C 4 alkoxy groups, carboxyl groups and/or nitro groups; C 1 -C 4 alkylenephenyl group or naphthyl group, and in the case of carboxylic acids of general formula I, also their esters of physiologically harmless alcohols, their amides of physiologically tolerable amines and their salts of physiologically compatible bases.
- the 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention are derivatives of the 9H-pyrido 3,4-b!indole derivatives, known a priori and often also referred to as ⁇ -carbolines, of general formula II ##STR3## in which U, V, X, R 1 , R 2 and R 3 have the above-mentioned meaning, which are pharmacologically active substances that affect the central nervous system and can be used as active ingredients in psychopharmaceutical agents (EP-A 0054 507 and EP-A 0239 669).
- the compounds according to the invention with their chemical structure are comparable to completely different substances known a priori, such as, for example, the cycloalkane derivatives known a priori from WO 92/16504, WO 93/11105, DE-A 42 27 790 or DE-A 42 42 390; the phenyl derivatives known a priori from WO 94/04522; the naphthyl derivatives known a priori from WO 92/05145,; the pyridine derivatives known a priori from WO 91/14676 and WO 94/02464; and the indole derivatives known a priori from WO 92/04321.
- the 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention can have as substituent R 2 , for example, a methoxy group, an ethoxy group, a tert-butyloxy group, an acetoxy group or a benzoyloxy group and/or as substituents R 3 and/or R 4 a phenyl radical, benzyl radical or phenyl radical optionally substituted in o-, m- or p-position by a C 1 -C 4 alkyl group (such as, for example, the methyl group), a C 1 -C 4 alkoxy group (such as, for example, the methoxy group, a chlorine atom, a fluorine atom, a trifluoromethyl group, a carboxyl group or a nitro group.
- substituent R 2 for example, a methoxy group, an ethoxy group, a tert-butyloxy group, an ace
- Carboxylic acids of general formula I can be esterified according to the invention with physiologically harmless alcohols.
- alcohols are, for example, alkanols with 1 to 6 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol or tert-butanol or cycloalkanols with up to 7 carbon atoms, such as cyclopentanol or cyclohexanol.
- alkanols with 1 to 6 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol or tert-butanol or cycloalkanols with up to 7 carbon atoms, such as cyclopentanol or cyclohexanol.
- they can also be amidated with amines according to the invention.
- suitable amines are C 1 -C 6 alkylamines, such as methylamine, ethylamine or isopropylamine, C 1 -C 6 dialkylamines such as dimethylamine, diethylamine or diisopropylamine or saturated N-heterocycles such as pyrrolidine, piperidine, N-methylpiperidine, piperazine or morpholine.
- C 1 -C 6 alkylamines such as methylamine, ethylamine or isopropylamine
- C 1 -C 6 dialkylamines such as dimethylamine, diethylamine or diisopropylamine or saturated N-heterocycles
- pyrrolidine piperidine, N-methylpiperidine, piperazine or morpholine.
- Such bases are, for example, alkali metal hydroxides, alkaline-earth metal hydroxides, alkali metal carbonates, alkaline-earth metal carbonates such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium carbonate, calcium hydroxide or calcium carbonate.
- suitable bases are also ammonia or amines such as methylamine, diethylamine, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine or tris-(hydroxymethyl)-methylamine.
- the 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention can be produced, for example, in a way known in the art from the 9H-pyrido 3,4-b!indole derivatives of general formula II known a priori, by the latter being alkylated with a reactive compound of general formula III
- W, Y and R 4 have the above-mentioned meaning and Q symbolizes a nucleofuge radical, and the compounds obtained are optionally converted into their esters, amides or salts.
- Suitable nucleofuge radicals Q are, for example, the acyl radicals of stronger carboxylic acids, such as trifluoroacetic acid, sulfonic acid radicals such as those of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid and especially the halogen atoms chlorine, bromine and iodine.
- carboxylic acids such as trifluoroacetic acid, sulfonic acid radicals such as those of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid and especially the halogen atoms chlorine, bromine and iodine.
- LTB 4 is a more important inflammation mediator for inflammatory diseases, in which leukocytes invade the diseased tissue.
- LTB 4 The effects of LTB 4 are triggered on the cellular plane by the binding of LTB 4 to a specific receptor.
- LTB 4 causes the adhesion of leukocytes to the blood vessel wall.
- LTB 4 is chemotactically active, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration.
- LTB 4 indirectly alters vascular permeability, whereby a synergism with prostaglandin E 2 is observed.
- LTB 4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
- Leukotrienes and especially LTB 4 are involved in skin diseases that accompany inflammatory processes (increased vascular permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne.
- Pathologically increased leukotriene concentrations are either causally involved in the development of many dermatides or there is a connection between the persistence of the dermatides and the leukotrienes.
- leukotriene concentrations were measured in, for example, the skin of patients with psoriasis, atopic dermatitis, allergic contact dermatitis, bullous pemphigoids, delayed pressure urticaria and allergic vasculitis.
- Leukotrienes and especially LTB 4 are also involved in diseases of internal organs, for which an acute or chronically inflammatory component was described, e.g., arthropathies (rheumatic arthritis); diseases of the respiratory tract (asthma and chronically obstructive lung diseases (OPD)); inflammatory intestinal diseases (ulcerous colitis and Crohn's disease), as well as damage after reperfusion (of heart, intestinal or kidney tissue), which develop by, at times, pathological obstruction of blood vessels, such as glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases.
- arthropathies rheumatic arthritis
- diseases of the respiratory tract asthma and chronically obstructive lung diseases (OPD)
- OPD chronically obstructive lung diseases
- inflammatory intestinal diseases e.g., glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases
- Leukotrienes and especially LTB 4 are also involved in the disease of multiple sclerosis and in the clinical appearance of shock (triggered by infections, burns or in complications in kidney dialysis or other perfusion techniques that are discussed separately).
- Leukotrienes and especially LTB 4 also have an effect on the formation of white blood cells in the bone marrow, on the growth of unstriped muscle cells, of keratinocytes and of B-lymphocytes. LTB 4 is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.
- leukemia or arteriosclerosis represent diseases with this appearance.
- the active ingredients and their form of administration of this invention are specific medicines in the diseases of humans and animals, in which especially leukotrienes play a pathological role.
- the new compounds are suitable for treating multiple sclerosis and the symptoms of shock.
- the production of the pharmaceutical agent specialties is carried out in the usual way by the active ingredients being converted with suitable additives into the desired form of administration, such as, for example: solutions, ointments, creams or plasters.
- the active ingredient concentration depends on the form of administration.
- an active ingredient concentration of 0.0001% to 3% is preferably used.
- the new compounds optionally in combination with the commonly used vehicles and adjuvants are also well-suited for the production of inhalants, which can be used for the treatment of allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
- the new substances are also suitable in the form of capsules, tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient and are administered orally or in the form of suspensions that preferably contain 1-200 mg of active ingredient per dosage unit and are administered rectally even for treating diseases of the internal organs, in which leukotrienes play an important role, such as, e.g.: diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
- the new compounds are also suitable for the treatment of diseases in which, depending on the leukotriene, the increased growth and the new formation of cells are emphasized.
- diseases in which, depending on the leukotriene, the increased growth and the new formation of cells are emphasized.
- leukemia increased growth of white blood cells
- arteriosclerosis increased growth of unstriped muscle cells of blood vessels.
- the new 9H-pyrido 3,4-b!indole derivatives can also be used in combination, such as, e.g., with lipoxygenase inhibitors, cyclooxygenase inhibitors, glucocorticoids, prostacyclin agonists, thromboxane antagonists, leukotriene-C 4 antagonists, leukotriene-D 4 antagonists, leukotriene-E 4 antagonists, leukotriene-F 4 antagonists, phosphodiesterase inhibitors, calcium antagonists, PAF antagonists or other known forms of treatment of the respective diseases.
- lipoxygenase inhibitors e.g., cyclooxygenase inhibitors, glucocorticoids, prostacyclin agonists, thromboxane antagonists, leukotriene-C 4 antagonists, leukotriene-D 4 antagonists, leukotriene-E 4 antagonists, leukotriene-F 4 antagonists, phosphodiesterase inhibitors
- IR 2980, 2940, 1710, 1650, 1480, 1450, 1300, 1190, 1100 cm -1 .
- IR 3400, 2940, 1650, 1610, 1570, 1480, 1380, 1360, 1200 cm -1 .
- IR 3340, 2980, 2930, 1710, 1640, 1580, 1480, 1450, 1370, 1310 cm -1 .
- IR 3480, 3060, 3020, 2930, 1740, 1650, 1610, 1580, 1480, 1450, 1370, 1330 cm -1 .
- IR 2978, 1734, 1653, 1503, 1467, 1268, 1104 cm -1 .
- IR 3400, 8060, 2950, 1645, 1610, 1480, 1365, 1290, 1105 cm -1 .
- IR 2978, 1735, 1654, 1503, 1471, 1299, 1268, 1168, 1105 cm -1 .
- IR 3400, 2930, 1751, 1654, 1472, 1365, 1269, 1138 cm -1 .
- IR 2977, 1702, 1559, 1500, 1300, 1268, 1235, 1107 cm -1 .
- IR 3400, 1680, 1530, 1468, 1380, 1345, 1290, 1235, 1105 cm -1 .
- IR 2979, 1745, 1654, 1469, 1299, 1105 cm -1 .
- IR 3400, 2992, 1664, 1577, 1497, 1453, 1364, 1138 cm -1 .
- the acid chloride that is thus obtained is taken up in dichloromethane, cooled to 0° C., and mixed with 1 ml of triethylamine and 2 ml of dimethylamine solution (33% in absolute ethanol).
- the reaction mixture is allowed to stand for 5 hours at room temperature, it is poured into water, mixed with saturated sodium chloride solution and extracted three times with 30 ml of dichloromethane each.
- the organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum.
- the crude product that is obtained is chromatographed on a silica gel column with dichloromethane/ethanol.
- IR 3440, 3340, 2930, 1 670, 1650, 1630, 1480, 1290, 1230, 1190 cm -1 and as a nonpolar fraction, 210 mg of 6-benzyloxy-4-hydroxymethyl-9- ⁇ 2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl ⁇ -9H-pyrido 3,4-b!indole-3-carboxylic acid lactone is obtained as a colorless oil.
- IR 1760, 1660, 1480, 1350, 1310, 1200 cm -1 .
- the crude product that is obtained is purified with a preparative silica gel plate with hexane-ethyl acetate, and 13 mg of 6-benzyloxy-4-(carboxymethoxymethyl)-9- ⁇ 2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl ⁇ -9H-pyrido 3,4-b!indole-carboxylic acid is obtained.
- IR 3400, 2940, 1730, 1660, 1640, 1480, 1400, 1290, 1230, 1190 cm -1 .
- IR 2980, 2930, 1720, 1660, 1650, 1512, 1580, 1100 cm -1 .
- the precipitated crystals are suctioned off, they are washed with a little acetonitrile, dried in a vacuum, and 130 mg of the trishydroxymethyl-aminomethane salt of 5-benzyloxy-4-methoxymethyl-9- ⁇ 2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl ⁇ -9H-pyrido- 3,4-b!indole-3-carboxylic acid is obtained as colorless crystals with a melting point of 171°-179° C.
- the precipitated crystals are suctioned off, washed with a little acetonitrile, it is dried in a vacuum, and 55 mg of the cyclohexyl salt of 5-benzyloxy-4-methoxymethyl-9- ⁇ 2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl ⁇ -9H-pyrido- 3,4-b!indole-3 carboxylic acid is obtained as colorless crystals with a melting point of 164°-179° C.
- IR 2980, 2930, 1720, 1700, 1663, 1630, 1340, 1110 cm -1 .
- IR 3420, 2930, 1748, 1650, 1620, 1610, 1340, 1250 cm -1 .
- reaction mixture is mixed with 0.1 ml of isopropanol and then with 0.1 ml of water, it is stirred for 2 hours at room temperature, filtered, and the filtrate is concentrated by evaporation in a vacuum.
- the residue is recrystallized from ethyl acetate, and 43 mg of 5-benzyloxy-4-methoxymethyl-9- ⁇ 2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl ⁇ -9H-pyrido 3,4-b!indole-3-carbaldehyde is obtained as colorless crystals with a melting point of 192°-197° C.
- IR 2935, 2720, 1695, 1655, 1615, 1570, 1103 cm -1 .
- IR 3360, 2939, 1665, 1580, 1466, 126, 1101 cm -1 .
- the crude product that is obtained is purified on a silica gel column with ethyl acetate-hexane, and 338 mg of 5-benzyloxy-4-methoxymethyl-9-(3-phenylpropyl)-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ether is obtained.
- IR 2980, 2940, 1730, 1615, 1580, 1500, 1460, 1300, 1265, 1160, 1100 cm -1 .
- IR 3600, 3100, 2930, 1745, 1655, 1625, 1610, 1575, 1495, 1450, 1270 cm -1 .
- IR 2980, 2935, 1718, 1665, 1630, 1580, 1468, 1303, 1268, 995 cm -1 .
- IR 3430, 2938, 1743, 1660, 1628, 1605, 1493, 1370, 1275, 990 cm -1 .
- IR(Film) 2979, 2932, 1732, 1613, 1578, 1499, 1463, 1371, 1298, 1267, 1242, 1162, 1108, 1049, 966, 785, 730, 697 cm -1 .
- IR(KBr) 2973, 2930, 1710, 1615, 1578, 1500, 1498, 1463, 1450, 1361, 1270, 1210, 1195, 1100, 1057, 1000, 750 cm -1 .
- Example 29 174 mg (0.352 mmol) of the compound that is presented according to Example 29 is reacted as described in Example 27 and worked up. 137 mg of yellow crystals (86%). Melting point 170°-172° C.
- IR(KBr) 3700-3100, 3100-2300, 3030, 2930, 1745, 1625, 1610, 1575, 1495, 1450, 1365, 1345, 1270, 1160, 1100, 1000, 785, 730, 697 cm -1 .
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
9H-Pyrido 3,4-b!indole compounds have a pronounced leukotriene-B4 antagonistic action, and thus show a completely different spectrum of activity than known β-carbolines.
Description
This application is a 377 of PCT/EP96/00213 filed Jan. 19, 1996. The invention relates to new 9H-pyrido 3,4-b!indole derivatives of general formula I ##STR1## in which U, V and W mean a carbon-carbon bond or a C1 -C6 alkylene group,
R1 represents a hydrogen atom, a hydroxy group or a carboxyl group, and
R2 symbolizes a hydrogen atom, a hydroxy group, a C1 -C4 alkoxy group, a C1 -C6 alkanoyloxy group or a C1 -C4 -ω-carboxyalkoxy group, or
R1 and R2 together are an oxycarbonyl group, and in which
X means a carbon-carbon bond or an oxygen,
Y means a carbon-carbon bond, the grouping --CONR' with R' in the meaning of a hydrogen atom or a C1 -C7 alkyl group that is optionally substituted by a carboxyl group, or the grouping ##STR2## with m and n in the meaning of numbers of a total of 3, 4 or 5, and Z in the meaning of a methylidine group or an aza group, and
R3 and R4 in each case symbolize a phenyl group optionally substituted by halogen atoms, trifluoromethyl groups, cyanide groups, C1 -C7 alkyl groups, C1 -C4 alkoxy groups, carboxyl groups and/or nitro groups; C1 -C4 alkylenephenyl group or naphthyl group, and in the case of carboxylic acids of general formula I, also their esters of physiologically harmless alcohols, their amides of physiologically tolerable amines and their salts of physiologically compatible bases.
The 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention are derivatives of the 9H-pyrido 3,4-b!indole derivatives, known a priori and often also referred to as β-carbolines, of general formula II ##STR3## in which U, V, X, R1, R2 and R3 have the above-mentioned meaning, which are pharmacologically active substances that affect the central nervous system and can be used as active ingredients in psychopharmaceutical agents (EP-A 0054 507 and EP-A 0239 669).
It has now been found that the 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention have, surprisingly enough, a pronounced leukotriene-B4 antagonistic action, and thus show a completely different spectrum of activity than the substances of general formula II known a priori.
Relative to their pharmacological action and their therapeutic applicability, the compounds according to the invention with their chemical structure are comparable to completely different substances known a priori, such as, for example, the cycloalkane derivatives known a priori from WO 92/16504, WO 93/11105, DE-A 42 27 790 or DE-A 42 42 390; the phenyl derivatives known a priori from WO 94/04522; the naphthyl derivatives known a priori from WO 92/05145,; the pyridine derivatives known a priori from WO 91/14676 and WO 94/02464; and the indole derivatives known a priori from WO 92/04321.
The 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention can have as substituent R2, for example, a methoxy group, an ethoxy group, a tert-butyloxy group, an acetoxy group or a benzoyloxy group and/or as substituents R3 and/or R4 a phenyl radical, benzyl radical or phenyl radical optionally substituted in o-, m- or p-position by a C1 -C4 alkyl group (such as, for example, the methyl group), a C1 -C4 alkoxy group (such as, for example, the methoxy group, a chlorine atom, a fluorine atom, a trifluoromethyl group, a carboxyl group or a nitro group.
Of the 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention, in the trials hitherto performed, especially the following substance groups were studied:
a) Compounds of general formula I with U in the meaning of a carbon-carbon bond, and in the latter preferably those whose substituent R1 is a carboxyl group, their esters, amides or salts.
b) Compounds of general formula I with V in the meaning of a methylene group and, among the latter, preferably compounds with R2 in the meaning of a hydrogen atom, an alkoxy group, such as, for example, the methoxy group or an alkanoxy group such as the acetoxy group.
c) Compounds of general formula I with X in the meaning of an oxygen atom and R3 in the meaning of an optionally substituted phenyl group or benzyl group.
d) Compounds of general formula I with W in the meaning of a C1 -C6 alkylene group, Y in the meaning of an N-alkylcarbanoyl group and R4 in the meaning of an optionally substituted C1 -C7 alkylenephenyl group.
e) Substances of general formula I with W in the meaning of a C1 -C6 alkylene group, Y in the meaning of an N-carboxymethyl-carbanoyl group and R4 in the meaning of an optionally substituted C1 -C4 alkylenephenyl group and
f) Substances of general formula I with W in the meaning of an N-carbonylpiperazino group and R4 in the meaning of an optionally substituted C1 -C4 alkylenephenyl group.
g) Compounds of general formula I with R3 and/or R4 in the meaning of a phenyl group, a p-nitrophenyl group, a benzyl group or a phenethyl group.
Within the framework of the hitherto performed trials, special attention was focussed on the compounds that in addition to features d, e or f also have all the features of groups a to c and g.
Carboxylic acids of general formula I can be esterified according to the invention with physiologically harmless alcohols. Such alcohols are, for example, alkanols with 1 to 6 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol or tert-butanol or cycloalkanols with up to 7 carbon atoms, such as cyclopentanol or cyclohexanol. On the other hand, they can also be amidated with amines according to the invention. In addition to ammonia itself, suitable amines are C1 -C6 alkylamines, such as methylamine, ethylamine or isopropylamine, C1 -C6 dialkylamines such as dimethylamine, diethylamine or diisopropylamine or saturated N-heterocycles such as pyrrolidine, piperidine, N-methylpiperidine, piperazine or morpholine. For salt formation of the carboxylic acids of general formula I according to the invention, all physiologically compatible inorganic or organic bases that are usually used for the production of pharmacologically active carboxylic acid salts are suitable. Such bases are, for example, alkali metal hydroxides, alkaline-earth metal hydroxides, alkali metal carbonates, alkaline-earth metal carbonates such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium carbonate, calcium hydroxide or calcium carbonate. On the other hand, suitable bases are also ammonia or amines such as methylamine, diethylamine, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine or tris-(hydroxymethyl)-methylamine.
The 9H-pyrido 3,4-b!indole derivatives of general formula I according to the invention can be produced, for example, in a way known in the art from the 9H-pyrido 3,4-b!indole derivatives of general formula II known a priori, by the latter being alkylated with a reactive compound of general formula III
Q--W--Y--R.sub.4 (III),
in which W, Y and R4 have the above-mentioned meaning and Q symbolizes a nucleofuge radical, and the compounds obtained are optionally converted into their esters, amides or salts.
Suitable nucleofuge radicals Q are, for example, the acyl radicals of stronger carboxylic acids, such as trifluoroacetic acid, sulfonic acid radicals such as those of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid and especially the halogen atoms chlorine, bromine and iodine.
The conditions under which the alkylation of 9H-pyrido 3,4-b!indole derivatives of general formula II is carried out are the same that are otherwise also used for alkylating amines and require no explanation. Also, the optionally subsequent esterification of the free carboxylic acids or alcohol and the optional amide formation from the free carboxylic acids is carried out under conditions that are familiar to each one skilled in the art.
It was already mentioned that the new alkylated 9H-pyrido 3,4-b!indole derivatives have a pronounced leukotriene-B4 -antagonistic activity. Consequently, they are active in an antiinflammatory, antiallergic and antiproliferative manner.
The physiological and especially the pathophysiological importance of leukotriene B4 is summarized in several new works: a) The Leukotrienes, Chemistry and Biology, eds., L. W. Chakrin, D. M. Bailey, Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelson, Sciences 237, 1171 (1987). d) C. W. Parker, Drug Development Research 10, 277 (1987). It follows from the above that LTB4 is a more important inflammation mediator for inflammatory diseases, in which leukocytes invade the diseased tissue.
The effects of LTB4 are triggered on the cellular plane by the binding of LTB4 to a specific receptor.
It is known concerning LTB4 that it causes the adhesion of leukocytes to the blood vessel wall. LTB4 is chemotactically active, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. In addition, based on its chemotactic activity, it indirectly alters vascular permeability, whereby a synergism with prostaglandin E2 is observed. LTB4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB4 are involved in skin diseases that accompany inflammatory processes (increased vascular permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne. Pathologically increased leukotriene concentrations are either causally involved in the development of many dermatides or there is a connection between the persistence of the dermatides and the leukotrienes. Considerably increased leukotriene concentrations were measured in, for example, the skin of patients with psoriasis, atopic dermatitis, allergic contact dermatitis, bullous pemphigoids, delayed pressure urticaria and allergic vasculitis.
Leukotrienes and especially LTB4 are also involved in diseases of internal organs, for which an acute or chronically inflammatory component was described, e.g., arthropathies (rheumatic arthritis); diseases of the respiratory tract (asthma and chronically obstructive lung diseases (OPD)); inflammatory intestinal diseases (ulcerous colitis and Crohn's disease), as well as damage after reperfusion (of heart, intestinal or kidney tissue), which develop by, at times, pathological obstruction of blood vessels, such as glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases.
Leukotrienes and especially LTB4 are also involved in the disease of multiple sclerosis and in the clinical appearance of shock (triggered by infections, burns or in complications in kidney dialysis or other perfusion techniques that are discussed separately).
Leukotrienes and especially LTB4 also have an effect on the formation of white blood cells in the bone marrow, on the growth of unstriped muscle cells, of keratinocytes and of B-lymphocytes. LTB4 is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.
For example, leukemia or arteriosclerosis represent diseases with this appearance.
By the antagonization of effects especially of LTB4, the active ingredients and their form of administration of this invention are specific medicines in the diseases of humans and animals, in which especially leukotrienes play a pathological role.
They are suitable in combination with the additives and media that are commonly used in galenical pharmaceutics for local treatment of diseases of the skin, in which leukotrienes play an important role, for example, contact dermatitis, eczemas of the most varied type, neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea, erythematosus cutaneous, psoriasis, lichen ruber planus et verrucosus and similar skin diseases.
In addition, the new compounds are suitable for treating multiple sclerosis and the symptoms of shock.
The production of the pharmaceutical agent specialties is carried out in the usual way by the active ingredients being converted with suitable additives into the desired form of administration, such as, for example: solutions, ointments, creams or plasters.
In the pharmaceutical agents that are thus formulated, the active ingredient concentration depends on the form of administration. In the case of lotions and ointments, an active ingredient concentration of 0.0001% to 3% is preferably used.
Moreover, the new compounds optionally in combination with the commonly used vehicles and adjuvants are also well-suited for the production of inhalants, which can be used for the treatment of allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
The new substances are also suitable in the form of capsules, tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient and are administered orally or in the form of suspensions that preferably contain 1-200 mg of active ingredient per dosage unit and are administered rectally even for treating diseases of the internal organs, in which leukotrienes play an important role, such as, e.g.: diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
In these new forms of administration, in addition to the treatment of diseases of internal organs with inflammatory processes, the new compounds are also suitable for the treatment of diseases in which, depending on the leukotriene, the increased growth and the new formation of cells are emphasized. Examples are leukemia (increased growth of white blood cells) or arteriosclerosis (increased growth of unstriped muscle cells of blood vessels.)
The new 9H-pyrido 3,4-b!indole derivatives can also be used in combination, such as, e.g., with lipoxygenase inhibitors, cyclooxygenase inhibitors, glucocorticoids, prostacyclin agonists, thromboxane antagonists, leukotriene-C4 antagonists, leukotriene-D4 antagonists, leukotriene-E4 antagonists, leukotriene-F4 antagonists, phosphodiesterase inhibitors, calcium antagonists, PAF antagonists or other known forms of treatment of the respective diseases.
The embodiments below are used for a more detailed explanation of the process according to the invention.
998 mg of 6-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-1-methylethyl-ester (2.4 mmol) is introduced into 10 ml of dry tetrahydrofuran and deprotonated at 0° C. with 72 mg of sodium hydride (80% suspension in oil) (2.4 mmol). Then, it is stirred for 20 minutes at room temperature, mixed with 630 mg of 2- N-methyl-N-(2-phenylethyl)-amino!-2-bromoacetamide (2.4 mmol)--dissolved in 10 ml of tetrahydrofuran--stirred for another 5 hours at room temperature, filtered on diatomaceous earth, and then the solvent is drawn off in a vacuum. The crude product that is obtained is recrystallized from dichloromethane/diethyl ether, and 1.22 g of 6-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)amino!-2-oxoethyl}-9H-pyrido- 3,4-b!indole-3-carboxylic acid-(1-methyl-ethyl)-ester is obtained.
IR=2980, 2940, 1710, 1650, 1480, 1450, 1300, 1190, 1100 cm-1.
211 mg of 6-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is mixed in 1 ml of methanol with 0.5 ml of aqueous 2N sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, the precipitated yellow reaction product is suctioned off, washed with water and diethyl ether and dried in a vacuum. 150 mg of 6-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid is obtained.
IR=3400, 2940, 1650, 1610, 1570, 1480, 1380, 1360, 1200 cm-1.
2.63 g of 6-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methyl-ethyl)-ester (6.5 mmol) is taken up in 50 ml of dry tetrahydrofuran and mixed for deprotonation with 235 mg of 80% sodium hydride suspension in oil (7.1 mmol). It is allowed to stir for 20 more minutes at room temperature, then 2.22 g of 6- N-methyl-N-(2-phenylethyl)-amino!-2-oxohexylbromide (7.1 mmol)--dissolved in 10 ml of tetrahydrofuran--is added. It is stirred for 12 hours at room temperature, mixed with 5 ml of 2N aqueous hydrochloric acid and diluted with water. It is then extracted with dichloromethane, the solvent is drawn off in a vacuum, and the crude product that is obtained is chromatographed on silica gel using hexane-ethyl acetate. 4.1 g of 6-benzyloxy-4-methoxymethyl-9{6- N-methyl-N-(2-phenylethyl)-amino!-2-oxohexyl}9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as a brownish oil.
IR=3340, 2980, 2930, 1710, 1640, 1580, 1480, 1450, 1370, 1310 cm-1.
350 mg of 6-benzyloxy-4-methoxymethyl-9-{6- N-methyl-N-(2-phenylethyl)-amino!-2-oxohexyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (0.55 mmol) is mixed in 10 ml of methanol with 1 ml of 2N aqueous sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, and the precipitated product is suctioned off. It is washed with water and then with diethyl ether, dried in a vacuum, and 212 mg of 6-benzyloxy-4-methoxymethyl-9-{6- N-methyl-N-(2-phenylethyl)-amino!-2-oxohexyl}-9H-pyrido- 3,4-b!-indole-3-carboxylic acid is obtained as a yellow, amorphous powder.
IR=3480, 3060, 3020, 2930, 1740, 1650, 1610, 1580, 1480, 1450, 1370, 1330 cm-1.
1000 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-1-methylethyl-ester (2.5 mmol) is introduced into 10 ml of dry tetrahydrofuran and deprotonated at 0° C. with 72 mg of sodium hydride (80% suspension in oil) (2.4 mmol). Then, it is stirred for 20 minutes at room temperature, mixed with 617 mg of 2- N-methyl-N-benzyl!-2-bromoacetamide (2.5 mmol)--dissolved in 3 ml of tetrahydrofuran--stirred for another 12 hours at room temperature, filtered on diatomaceous earth, and then the solvent is drawn off in a vacuum. The crude product that is obtained is chromatographed on hexane-ethyl acetate, and 890 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-benzylamino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methyl-ethyl)-ester is obtained as an amorphous powder with a melting point of 155°-157° C.
IR=2978, 1734, 1653, 1503, 1467, 1268, 1104 cm-1.
460 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-benzyl-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is mixed in 3 ml of methanol with 1 ml of aqueous 2N sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, the precipitated reaction product is suctioned off, washed with water and diethyl ether and dried in a vacuum. 370 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-benzyl-amino!-2-oxoethyl}-9H-pyrido- 3,4-b!indole-3-carboxylic acid (decomposition starting at 239°) is obtained.
IR=3400, 8060, 2950, 1645, 1610, 1480, 1365, 1290, 1105 cm-1.
786 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (1.95 mmol) is taken up in 50 ml of dry tetrahydrofuran and mixed for deprotonation with 482 mg of 80% sodium hydride suspension in oil (20 mmol). It is allowed to stir for 20 more minutes at room temperature, then 500 mg of 2- N-ethyl-N-benzyl!-2-bromoacetamide (1.95 mmol)--dissolved in 10 ml of tetrahydrofuran--is added. It is stirred for 48 hours at room temperature, mixed with 5 ml of 2N aqueous hydrochloric acid and diluted with water. It is then extracted with dichloromethane, the solvent is drawn off in a vacuum, and the crude product that is obtained is recrystallized on ethyl acetate. 540 mg of 5-benzyloxy-4-methoxymethyl-9{2- N-ethyl-N-benzyl-amino!-2-oxo-ethyl}9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester with a melting point of 142°-144° C. is obtained.
IR=2978, 1735, 1654, 1503, 1471, 1299, 1268, 1168, 1105 cm-1.
300 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-ethyl-N-benzyl-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl-ester (0.5 mmol) is mixed in 2 ml of methanol with 1 ml of 2N aqueous sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, and the precipitated product is suctioned off. It is washed with water and then with diethyl ether, dried in a vacuum, and 210 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-ethyl-N-benzyl-amino!-2-oxoethyl}-9H-pyrido 3,4-b!-indole-3-carboxylic acid (decomposition starting from 242° C.) is obtained.
IR=3400, 2930, 1751, 1654, 1472, 1365, 1269, 1138 cm-1.
1000 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-1-methylethyl-ester is introduced into 10 ml of dry tetrahydrofuran and deprotonated at 0° C. with 78 mg of sodium hydride (80% suspension in oil) (2.6 mmol). Then, it is stirred for 20 minutes at room temperature, mixed with 697 mg of N-phenyl-piperazino-bromoacetamide (2.4 mmol)--dissolved in 3 ml of tetrahydrofuran--stirred for 5 hours at room temperature, filtered on diatomaceous earth, and then the solvent is drawn off in a vacuum. The crude product that is obtained is chromatographed on diatomaceous earth with dichloromethane/diethyl ether, and 789 mg of 5- (N-phenyl-piperazino-2-oxethyl!-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methyl-ethyl)-ester with a melting point of 256.2° C. is obtained.
IR=2977, 1702, 1559, 1500, 1300, 1268, 1235, 1107 cm-1.
700 mg of 5-benzyloxy-4-methoxymethyl-9- (N-phenyl-piperazino)-2-oxoethyl!-9H-pyrido 3.4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is mixed in 1 ml of methanol with 1 ml of aqueous 2N sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, the precipitated yellow reaction product is suctioned off, washed with water and diethyl ether and dried in a vacuum. 530 mg of 5-benzyloxy-4-methoxymethyl-9- ( N-phenylpiperazino)-2-oxoethyl!-9H-pyrido 3,4-b!indole-3-carboxylic acid is obtained (decomposition at 219° C.).
IR=3400, 1680, 1530, 1468, 1380, 1345, 1290, 1235, 1105 cm-1.
605 g of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methyl-ethyl)-ester (1.5 mmol) is taken up in 10 ml of dry tetrahydrofuran and mixed for deprotonation with 48 mg of 80% sodium hydride suspension in oil (1.6 mmol). It is allowed to stir for 20 more minutes at room temperature, then 500 mg of 2- N-(2-ethoxy-2-oxo-ethyl)-N-(benzyl)-!-2-bromoacetamide (1.5 mmol)--dissolved in 10 ml of tetrahydrofuran--is added. It is stirred for 5 hours at room temperature, mixed with 5 ml of 2N aqueous hydrochloric acid and diluted with water. It is then extracted with dichloromethane, the solvent is drawn off in a vacuum, and the crude product that is obtained is chromatographed on silica gel using dichloromethane/diethyl ether. 378 mg of 5-benzyloxy-4-methoxymethyl-9{2- N-(2-ethoxy-2-oxo-ethyl)-N-(benzyl)-amino!-2-oxoethyl}9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester with a melting point of 122.4° C. is obtained.
IR=2979, 1745, 1654, 1469, 1299, 1105 cm-1.
200 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-(2-ethoxy-2-oxo-ethyl)-N-(benzyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (0.3 mmol) is mixed in 2 ml of methanol with 1 ml of 2N aqueous sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, and the precipitated product is suctioned off. It is washed with water and then with diethyl ether, dried in a vacuum and 120 mg of 6-benzyloxy-4-methoxymethyl-9-{6- N-carboxymethyl-N-(benzyl)-amino!-2-oxohexyl}-9H-pyrido 3,4-b!-indole-3-carboxylic acid is obtained as a yellow, amorphous powder (decomposition starting from 245° C. ).
IR=3400, 2992, 1664, 1577, 1497, 1453, 1364, 1138 cm-1.
600 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid is mixed in 30 ml of dichloromethane and at 0° C. with 0.087 ml of thionyl chloride and then with 0.09 ml of dimethylformamide. The reaction mixture is allowed to stir for 12 hours at room temperature, then drawn off in a vacuum, mixed again with 30 ml of dichloromethane, and the solvent is drawn off again in a vacuum. The acid chloride that is thus obtained is taken up in dichloromethane, cooled to 0° C., and mixed with 1 ml of triethylamine and 2 ml of dimethylamine solution (33% in absolute ethanol). The reaction mixture is allowed to stand for 5 hours at room temperature, it is poured into water, mixed with saturated sodium chloride solution and extracted three times with 30 ml of dichloromethane each. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The crude product that is obtained is chromatographed on a silica gel column with dichloromethane/ethanol. As a polar fraction, 210 mg of 6-benzyloxy-4-hydroxymethyl-9-{2-(N-methyl-N-(phenylethyl)-amino)-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-dimethylamide is obtained as a colorless solid (decomposition starting from 235° C.).
IR=3440, 3340, 2930, 1 670, 1650, 1630, 1480, 1290, 1230, 1190 cm-1 and as a nonpolar fraction, 210 mg of 6-benzyloxy-4-hydroxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid lactone is obtained as a colorless oil.
IR=1760, 1660, 1480, 1350, 1310, 1200 cm-1.
54 mg of 6-benzyloxy-4-hydroxymethyl-9-{2- N-methyl-N-(2-(phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-dimethylamide is mixed in 5 ml of dry tetrahydrofuran at 0° C. with 6 mg of 80% sodium hydride suspension in oil, stirred for 15 minutes, and then 19 mg of bromoacetic acid-t-butyl ester is added. It is stirred for 3 hours at room temperature, filtered, and the crude product that is obtained is purified by preparative thin-layer chromatography on a silica gel plate using hexane-ethyl acetate 1:1. The product that is obtained is taken up in 3 ml of methanol, mixed with 1 ml of 10% sodium hydroxide solution and allowed to stand for 12 hours at room temperature. Then, the reaction mixture is diluted with water, neutralized with dilute solution and extracted with ethyl acetate. The crude product that is obtained is purified with a preparative silica gel plate with hexane-ethyl acetate, and 13 mg of 6-benzyloxy-4-(carboxymethoxymethyl)-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-carboxylic acid is obtained.
IR=3400, 2940, 1730, 1660, 1640, 1480, 1400, 1290, 1230, 1190 cm-1.
a) A solution of 1.72 g of N-methyl-N-phenyl-ethylamine in 18 ml of dichloromethane is added in drops to a solution of 1 g of bromoacetyl chloride in 3.7 ml of dichloromethane at -25° C. within one hour. It is stirred for another 15 minutes at -25° C., and the reaction mixture is poured into a mixture of 100 ml of dichloromethane and 10 ml of water. The organic phase is washed with dilute hydrochloric acid and then with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.9 g of N-methyl-N-2-phenylethyl-2-bromoacetamide is obtained as a crude product.
b) 2.1 g of 5-benzyloxy-4-methoxymethyl-9H-pyrido- 3,4-b!indole-3-carboxylic acid-(1-methylethyl)ester is added to a suspension of 168 mg of sodium hydride (80% in mineral oil) in 25 ml of tetrahydrofuran at 0° C., it is stirred for 10 minutes at 0° C., then mixed with a solution of 1.6 g of N-methyl-N-2-phenylethyl-2-bromoacetamide and stirred for 18 hours at 24° C. Then, it is suctioned off on Celite, concentrated by evaporation in a vacuum, and the residue is purified by chromatography on silica gel. 2.8 g of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as weak, yellowish crystals with a melting point of 146°-147° C.
IR=2980, 2930, 1720, 1660, 1650, 1512, 1580, 1100 cm-1.
120 ml of an aqueous 0.5N lithium hydroxide solution is added to a solution of 7 g of the isopropylester, produced according to Example 1, in 120 ml of ethanol and 120 ml of tetrahydrofuran, and it is stirred for 6 hours at 60° C. under argon. Then, it is cooled to 20° C. and acidified to pH 3 with a 10% sulfuric acid solution. It is diluted with ethyl acetate, shaken with brine, dried with Na2 SO4 and concentrated by evaporation in a vacuum. The solid residue is crystallized from an ethanol/diethyl ether mixture. In this case, 5 g of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenethyl)amino!-2-oxyethyl}-β-carboline-3-carboxylic acid is obtained as pale yellow-colored crystals with a melting point of 167°-175° C.
IR (KBr): 3430, 2930, 1750, 1660, 1615, 1103 cm-1.
0.035 ml of an aqueous solution of 822.5 mg of trishydroxymethyl-aminomethane in 1.5 ml of water is added to a solution of 100 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid in 11 ml of acetonitrile at 80° C., it is stirred for one hour at 80° C., for one hour at 55° C., 3 hours at 45° C. and 48 hours at 24° C. The precipitated crystals are suctioned off, they are washed with a little acetonitrile, dried in a vacuum, and 130 mg of the trishydroxymethyl-aminomethane salt of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido- 3,4-b!indole-3-carboxylic acid is obtained as colorless crystals with a melting point of 171°-179° C.
9.9 mg of cyclohexylamine is added to a solution of 54 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid in 2 ml of acetonitrile and 0.5 ml of tetrahydrofuran at 80° C., it is stirred for one hour at 80° C., for one hour at 55° C., for three hours at 45° C. and for 48 hours at 22° C. The precipitated crystals are suctioned off, washed with a little acetonitrile, it is dried in a vacuum, and 55 mg of the cyclohexyl salt of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido- 3,4-b!indole-3 carboxylic acid is obtained as colorless crystals with a melting point of 164°-179° C.
4.4 g of 4-methoxymethyl-5-(4-nitrophenoxy)-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is added to a suspension of 315 mg of sodium hydride (80% suspension in mineral oil) and 50 ml of tetrahydrofuran at 0° C., it is stirred for 15 minutes at 0° C., then mixed with a solution of 3.1 g of N-methyl-N-2-phenylethyl-2-bromoacetamide in 10 ml of tetrahydrofuran and stirred for 20 hours at 24° C.
Then, it is filtered on Celite, the filtrate is concentrated by evaporation in a vacuum, and the crude product that is obtained is purified by chromatography on a silica gel column with ethyl acetate. 2.9 g of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester, which has a melting point of 187°-188° C. after recrystallization from ethanol/tetrahydrofuran, is obtained.
IR=2980, 2930, 1720, 1700, 1663, 1630, 1340, 1110 cm-1.
10 ml of an aqueous 0.5N lithium hydroxide solution is added to a solution of 610 mg of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid (1-methyl-ethyl)-ester in 10 ml of methanol and 10 ml of tetrahydrofuran, and it is stirred for 24 hours at 50° C. Then, it is cooled to 20° C., acidified with 10% aqueous sulfuric acid and diluted with ethyl acetate. The solution that is obtained is washed twice with saturated sodium chloride solution dried on sodium sulfate and evaporated to dryness in a vacuum. The crude product that is obtained is recrystallized from ethanol/tetrahydrofuran, and 360 mg of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid is obtained as pale yellowish crystals with a melting point of 231°-232° C.
IR=3420, 2930, 1748, 1650, 1620, 1610, 1340, 1250 cm-1.
a) 200 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is dissolved in 3 ml of tetrahydrofuran. Then, 0.29 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is added in drops to the solution at 0° C., and it is stirred for 30 minutes at 0° C. Then, the reaction mixture is mixed with 0.1 ml of isopropanol and then with 0.1 ml of water, it is stirred for 2 hours at room temperature, filtered, and the filtrate is concentrated by evaporation in a vacuum. The residue is recrystallized from ethyl acetate, and 43 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carbaldehyde is obtained as colorless crystals with a melting point of 192°-197° C.
IR=2935, 2720, 1695, 1655, 1615, 1570, 1103 cm-1.
b) 25 mg of sodium borohydride is added to a solution of 35 mg of 5-benzyloxy-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carbaldehyde in 1 ml of tetrahydrofuran at 0° C., and it is then stirred for 3 hours at 0° C. Then, the reaction mixture is poured into ice water and extracted three times with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation in a vacuum. 34 mg of 5-benzyloxy-3-hydroxymethyl-4-methoxymethyl-9-{2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl}-9H-pyrido 3,4-b!indole is obtained.
IR=3360, 2939, 1665, 1580, 1466, 126, 1101 cm-1.
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 20 ml of dimethylformamide, mixed with 597 mg of 3-phenylpropyl bromide and 40 mg of sodium hydride (60% suspension in oil), and it is stirred for one hour at room temperature. 300 ml of methyl-tert-butyl ether is added to the reaction mixture, and the organic phase is washed with 20% citric acid and saturated sodium chloride solution. The organic phase is dried on sodium sulfate and evaporated to dryness in a vacuum. The crude product that is obtained is purified on a silica gel column with ethyl acetate-hexane, and 338 mg of 5-benzyloxy-4-methoxymethyl-9-(3-phenylpropyl)-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ether is obtained.
IR=2980, 2940, 1730, 1615, 1580, 1500, 1460, 1300, 1265, 1160, 1100 cm-1.
Under the conditions of Example 2, 314 mg of 5-benzyloxy-4-methoxymethyl-9-(3-phenylpropyl)-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is saponified, worked up, and recrystallization from ethanol, 262 mg of 5-benzyloxy-4-methoxymethyl-9-(3-phenylpropyl)-9H-pyrido 3,4-b!indole-3-carboxylic acid with a melting point of 132° C. is obtained.
IR=3600, 3100, 2930, 1745, 1655, 1625, 1610, 1575, 1495, 1450, 1270 cm-1.
10 mg of an 80% suspension of sodium hydride in oil is mixed with 10 ml of tetrahydrofuran and to 0° C. 404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is added to the suspension, it is stirred for 10 minutes at 0° C., mixed with 406 mg of 6-(4-methoxyphenyl)-hexyl bromide, and the reaction mixture is stirred for 16 hours at room temperature. After the reaction mixture is worked up as described, 330 mg of 5-benzyloxy-4-methoxymethyl-9- 6-(4-methoxyphenyl)-hexyl!-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
A solution of 1.096 g of 5-benzyloxy-4-methyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (2.93 mmol) in 2.9 ml of tetrahydrofuran is added to a suspension of 92.2 mg of sodium hydride (3.03 mmol; 80% in mineral oil) at 0° C. under nitrogen, and it is stirred for 10 minutes at 0° C. Then, 750 mg (2.93 mmol) of N-methyl-N-phenylethyl-2-bromoacetamide is added, and it is then stirred for 18 hours at 24° C. It is filtered off on Celite, the filtrate is concentrated by evaporation in a vacuum, and the crude product that is thus obtained is purified on a silica gel column with hexane/0-100% ethyl acetate. In this way, 1.24 g of 5-benzyloxy-4-methyl-9-(2- N-methyl-N-(2-phenylethyl)-amino!-2-oxoethyl)-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as an amorphous, yellowish-colored solid with a melting point of 69°-74° C.
IR=2980, 2935, 1718, 1665, 1630, 1580, 1468, 1303, 1268, 995 cm-1.
5.5 ml of a 0.5N lithium hydroxide solution is added to a solution of 300 mg (0.546 mmol) of the ester, produced according to Example 25, in 11 ml of a mixture of methanol and tetrahydrofuran at a 1:1 ratio. After 18 hours of stirring at 24° C., the reaction mixture is acidified with a 1N hydrochloric acid solution to pH 4, saturated with sodium chloride and extracted three times with 100 ml of tetrahydrofuran each. The combined organic phases are dried on sodium sulfate and concentrated by evaporation after filtration in a vacuum. The crude product that is thus obtained is recrystallized from tetrahydrofuran. In this way, 155.2 mg of 5-benzyloxy-4-methyl-9-{2-(N-methyl-N-(2-phenylethylamino!-2-oxoethyl}-9H-pyrido 3,4-b!indole-3-carboxylic acid is obtained as yellowish-colored crystals with a melting point of 136° C.
IR=3430, 2938, 1743, 1660, 1628, 1605, 1493, 1370, 1275, 990 cm-1.
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 15 ml of dimethylformamide and mixed with 217 mg (1.1 mmol) of cinnamyl bromide and 358 mg (1.1 mmol) of cesium carbonate. It is stirred for 48 hours at room temperature, the reaction mixture is worked up, as described in Example 26, and after chromatography, 210 mg of 5-benzyloxy-4-methoxymethyl-9-cinnamoyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
IR(Film): 2979, 2932, 1732, 1613, 1578, 1499, 1463, 1371, 1298, 1267, 1242, 1162, 1108, 1049, 966, 785, 730, 697 cm-1.
200 mg (0.384 mmol) of the compound that is presented according to Example 27 is added to 10 ml of methanol and mixed with 10 ml of a mixture of KOH, MeOH and H2 O. After stirring overnight at 50° C., starting material is still present. Another 5 ml of the mixture is added, and the batch is stirred over the weekend at 50° C. The reaction mixture is diluted with 30 ml of water, and the methanol is concentrated by evaporation. The aqueous phase is acidified to pH 4 with 10% H2 SO4. After 10 minutes of stirring, the precipitated product is suctioned off, washed with water and dried in a vacuum in a drying oven at 50° C. 147 mg of yellow crystals (80%), melting point 110°-112° C.
IR(KBr): 3700-3120, 3120-2200, 3030, 2930, 1747, 1629, 1610, 1578, 1497, 1465, 1455, 1365, 1345, 1270, 1160, 1108, 968, 787, 750, 697 cm-1.
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 15 ml of dimethylformamide and mixed with 188 mg (1.1 mmol) of benzyl bromide and 358 mg of cesium carbonate. It is stirred for 48 hours at room temperature, the reaction mixture s worked up as described in Example 26, and after chromatography, 194 mg of 5-benzyloxy-4-methoxymethyl-9-benzyl-9H-pyrido 3,4-b!indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
IR(KBr)=2973, 2930, 1710, 1615, 1578, 1500, 1498, 1463, 1450, 1361, 1270, 1210, 1195, 1100, 1057, 1000, 750 cm-1.
174 mg (0.352 mmol) of the compound that is presented according to Example 29 is reacted as described in Example 27 and worked up. 137 mg of yellow crystals (86%). Melting point 170°-172° C.
IR(KBr)=3700-3100, 3100-2300, 3030, 2930, 1745, 1625, 1610, 1575, 1495, 1450, 1365, 1345, 1270, 1160, 1100, 1000, 785, 730, 697 cm-1.
Claims (4)
1. A 9H-Pyrido 3,4-b!indole compound of formula I ##STR4## in which U, V and W mean a single bond or a C1 -C6 alkylene group,
R1 represents a hydrogen atom, a hydroxy group or a carboxyl group, and
R2 is a hydrogen atom, a hydroxy group, a C1 -C4 alkoxy group, a C1 -C6 alkanoyloxy group or a C1 -C4 -ω-carboxyalkoxy group, or
R1 and R2 together are an oxycarbonyl group,
X means a single bond or an oxygen atom,
Y means a single bond, the grouping --CONR with R being a hydrogen atom or a C1 -C7 alkyl group that is optionally substituted by a carboxyl group, or the grouping ##STR5## with m and n having numbers of a total of 3, 4 or 5, and Z meaning a methylidine group or an aza group,
R3 and R4 in each case is a phenyl group optionally substituted by halogen atoms, trifluoromethyl groups, C1 -C7 alkyl groups, C1 -C4 alkoxy groups, carboxyl groups and/or nitro groups; a C1 -C4 alkylenephenyl group or a naphthyl group, or a carboxylic acid of formula I, or an ester of physiologically harmless alcohol, or an amide of physiologically tolerable amine or a salt of physiologically compatible base,
with the proviso that where W is a single bond, Y is not --CONR1.
2. A compound according to claim 1, wherein W is a C1-6 -alkylene group.
3. A pharmaceutical composition, comprising a 9H-pyrido- 3,4-b!indole compound of formula I according to claim 1, and a physiologically acceptable carrier.
4. A process for the production of a 9H-pyrido 3,4-b!indole compound of formula I according to claim 1, comprising alkylating a 9H-pyrido 3,4-b!indole compound of formula II ##STR6## in which U, V, X, R1, R2 and R3 have the meaning mentioned in claim 1, with a reactive compound of formula III
Q--W--Y--R.sub.4 (III),
in which W, Y and R4 have the meaning mentioned in claim 1 and Q symbolizes a nucleofuge radical, and optionally converting the compounds that into their esters, amides or salts.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19502753A DE19502753A1 (en) | 1995-01-23 | 1995-01-23 | New 9H-pyrido [3,4-b] indole derivatives |
DE19502753.1 | 1995-01-23 | ||
PCT/EP1996/000213 WO1996022989A1 (en) | 1995-01-23 | 1996-01-19 | Novel 9h-pyrido[3,4-b]indol derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
US5880126A true US5880126A (en) | 1999-03-09 |
Family
ID=7752591
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/875,090 Expired - Fee Related US5880126A (en) | 1995-01-23 | 1996-01-19 | 9H-Pyridu ((3,4-b) indole derivatives |
Country Status (6)
Country | Link |
---|---|
US (1) | US5880126A (en) |
EP (1) | EP0805810A1 (en) |
JP (1) | JPH10512579A (en) |
CA (1) | CA2210501A1 (en) |
DE (1) | DE19502753A1 (en) |
WO (1) | WO1996022989A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2823975A1 (en) * | 2001-04-27 | 2002-10-31 | Sanofi Synthelabo | NEW USE OF PYRIDOINDOLONE |
EP1571193A1 (en) * | 2002-12-12 | 2005-09-07 | Idemitsu Kosan Co., Ltd. | Organic electroluminescent device material and organic electroluminescent device using same |
US20050222192A1 (en) * | 2002-10-23 | 2005-10-06 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics |
US20050288318A1 (en) * | 2002-10-23 | 2005-12-29 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics |
US20070129365A1 (en) * | 2004-04-21 | 2007-06-07 | Sanofi-Aventis | 6-Substituted pyridoindolone derivatives, production and therapeutic use thereof |
US20070293536A1 (en) * | 2003-10-03 | 2007-12-20 | Amgen Inc. | Salts and polymorphs of a potent antidiabetic compound |
US20080262020A1 (en) * | 2005-10-20 | 2008-10-23 | Sanofi-Aventis | 6-Heteroarylpyridoindolone Derivatives, Their Preparation and Therapeutic Use Thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2194213T3 (en) * | 1996-08-09 | 2003-11-16 | Boehringer Ingelheim Pharma | BETA-CARBOLINAS-4- REPLACED IN QUALITY OF IMMUNOMODULATORS. |
WO2010068794A2 (en) | 2008-12-10 | 2010-06-17 | The General Hospital Corporation | Hif inhibitors and use thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB950509A (en) * | 1961-03-28 | 1964-02-26 | Searle & Co | Improvements in or relating to piperazides |
US4719210A (en) * | 1985-10-04 | 1988-01-12 | Schering Aktiengesellschaft | 3-vinyl and 3-thyinyl-beta-carbolines, and their use as benzodiazepine receptor antagonists or agonists |
DE4223164A1 (en) * | 1991-07-11 | 1993-01-28 | Schering Ag | New 9-carbamoyl-beta-carboline derivs. - used as benzodiazepine antagonists, inverse agonists and agonists for treating neuro:degenerative and psychiatric disorders |
US5414002A (en) * | 1986-03-20 | 1995-05-09 | Schering Aktiengesellschaft | 5- or 6-substituted β-carboline-3-carboxylic acid esters |
US5506234A (en) * | 1991-09-13 | 1996-04-09 | Schering Aktiengesellschaft | β-carboline derivatives for use as pharmaceutical agents |
-
1995
- 1995-01-23 DE DE19502753A patent/DE19502753A1/en not_active Withdrawn
-
1996
- 1996-01-19 WO PCT/EP1996/000213 patent/WO1996022989A1/en not_active Application Discontinuation
- 1996-01-19 JP JP8522605A patent/JPH10512579A/en active Pending
- 1996-01-19 CA CA002210501A patent/CA2210501A1/en not_active Abandoned
- 1996-01-19 US US08/875,090 patent/US5880126A/en not_active Expired - Fee Related
- 1996-01-19 EP EP96901309A patent/EP0805810A1/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB950509A (en) * | 1961-03-28 | 1964-02-26 | Searle & Co | Improvements in or relating to piperazides |
US4719210A (en) * | 1985-10-04 | 1988-01-12 | Schering Aktiengesellschaft | 3-vinyl and 3-thyinyl-beta-carbolines, and their use as benzodiazepine receptor antagonists or agonists |
US5414002A (en) * | 1986-03-20 | 1995-05-09 | Schering Aktiengesellschaft | 5- or 6-substituted β-carboline-3-carboxylic acid esters |
DE4223164A1 (en) * | 1991-07-11 | 1993-01-28 | Schering Ag | New 9-carbamoyl-beta-carboline derivs. - used as benzodiazepine antagonists, inverse agonists and agonists for treating neuro:degenerative and psychiatric disorders |
US5506234A (en) * | 1991-09-13 | 1996-04-09 | Schering Aktiengesellschaft | β-carboline derivatives for use as pharmaceutical agents |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6967203B2 (en) | 2001-04-27 | 2005-11-22 | Sanofi-Aventis | Use of pyridoindolone derivatives for preparing anticancer medicines |
US7524857B2 (en) | 2001-04-27 | 2009-04-28 | Sanofi-Aventis | Pharmaceutical combinations based on pyridoindolone derivatives and anticancer agents |
US20050272760A1 (en) * | 2001-04-27 | 2005-12-08 | Sanofi-Aventis | Use of pyridoindolone derivatives for the preparation of medicinal products |
WO2002087574A3 (en) * | 2001-04-27 | 2003-02-13 | Sanofi Synthelabo | Use of pyridoindolone derivatives for preparing anticancer medicines |
US20040122036A1 (en) * | 2001-04-27 | 2004-06-24 | Bernard Bourrie | Pharmaceutical combinations based on pyridoindolone derivatives and anticancer agents |
US20040122027A1 (en) * | 2001-04-27 | 2004-06-24 | Bernard Bourrie | Use of pyridoindolone derivatives for preparing anticancer medicines |
FR2823975A1 (en) * | 2001-04-27 | 2002-10-31 | Sanofi Synthelabo | NEW USE OF PYRIDOINDOLONE |
KR100847413B1 (en) * | 2001-04-27 | 2008-07-18 | 사노피-아벤티스 | Pharmaceutical Combinations Based on Pyridoindolone Derivatives and Anticancer Agents |
WO2002087574A2 (en) * | 2001-04-27 | 2002-11-07 | Sanofi-Synthelabo | Use of pyridoindolone derivatives for preparing anticancer medicines |
WO2002087575A1 (en) * | 2001-04-27 | 2002-11-07 | Sanofi-Synthelabo | Pharmaceutical combinations based on pyridoindolone derivatives and anticancer agents |
US7160895B2 (en) | 2001-04-27 | 2007-01-09 | Sanofi-Aventis | Use of pyridoindolone derivatives for the preparation of medicinal products |
US20080214538A1 (en) * | 2002-10-23 | 2008-09-04 | Sanofi-Aventis | Pyridoindolone Derivatives Substituted in the 3-Position by a Phenyl, Their Preparation and Their Application in Therapeutics |
US8012991B2 (en) | 2002-10-23 | 2011-09-06 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics |
CN100345850C (en) * | 2002-10-23 | 2007-10-31 | 赛诺菲-安万特 | Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics |
US7816368B2 (en) | 2002-10-23 | 2010-10-19 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics |
US20050288318A1 (en) * | 2002-10-23 | 2005-12-29 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics |
US7390818B2 (en) | 2002-10-23 | 2008-06-24 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a phenyl, their preparation and their application in therapeutics |
US20050222192A1 (en) * | 2002-10-23 | 2005-10-06 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics |
US7456193B2 (en) | 2002-10-23 | 2008-11-25 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics |
EP1571193A1 (en) * | 2002-12-12 | 2005-09-07 | Idemitsu Kosan Co., Ltd. | Organic electroluminescent device material and organic electroluminescent device using same |
EP1571193A4 (en) * | 2002-12-12 | 2008-05-07 | Idemitsu Kosan Co | Organic electroluminescent device material and organic electroluminescent device using same |
US20070293536A1 (en) * | 2003-10-03 | 2007-12-20 | Amgen Inc. | Salts and polymorphs of a potent antidiabetic compound |
US7812165B2 (en) | 2004-04-21 | 2010-10-12 | Sanofi-Aventis | 6-substituted pyridoindolone derivatives, production and therapeutic use thereof |
US20070129365A1 (en) * | 2004-04-21 | 2007-06-07 | Sanofi-Aventis | 6-Substituted pyridoindolone derivatives, production and therapeutic use thereof |
US20080262020A1 (en) * | 2005-10-20 | 2008-10-23 | Sanofi-Aventis | 6-Heteroarylpyridoindolone Derivatives, Their Preparation and Therapeutic Use Thereof |
US8063061B2 (en) | 2005-10-20 | 2011-11-22 | Sanofi-Aventis | 6-heteroarylpyridoindolone derivatives, their preparation and therapeutic use thereof |
Also Published As
Publication number | Publication date |
---|---|
EP0805810A1 (en) | 1997-11-12 |
CA2210501A1 (en) | 1996-08-01 |
JPH10512579A (en) | 1998-12-02 |
DE19502753A1 (en) | 1996-07-25 |
WO1996022989A1 (en) | 1996-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SU1169534A3 (en) | Method of obtaining derivatives of trisubstituted imidazoles of their salts with base | |
AU714312B2 (en) | Bicyclic amino derivatives and PGD2 antagonist containing them | |
FI102895B (en) | A process for the preparation of therapeutically active 5- (phenylsulfonylamino) - and 5- (phenylsulfonylaminocarbonyl) pyridine-2-carboxylic acid amides | |
NO853695L (en) | ISOXAZOLCARBOXYLIC ACID DERIVATIVES, PREPARATION AND USE THEREOF. | |
JP2007505942A (en) | Benzimidazole derivatives: production and pharmaceutical applications | |
MX2008015768A (en) | New cxcr2 inhibitors. | |
US5880126A (en) | 9H-Pyridu ((3,4-b) indole derivatives | |
JP2000507588A (en) | Amidinohydrazone as a protease inhibitor | |
US5587505A (en) | Triterpene derivatives and endothelin-receptor antagonists containing the same | |
US5559134A (en) | Leukotriene-B4 antagonists, process for their production and their use as pharmaceutical agents | |
US4886806A (en) | Flavone-3-carboxylic acids compounds and pharmaceutical compositions containing them | |
HU192868B (en) | Process for producing particularly antiasthmatic medicine preparations | |
US4077998A (en) | Phthaloyl amino acid hydroxamic acids | |
JPH06271543A (en) | New pyridinium derivative | |
FR2472561A1 (en) | 4-GUANIDINOMETHYLCYCLOHEXANE CARBOXYLIC ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION | |
EP0149419B1 (en) | Acylindole derivatives and pharmaceutical compositions containing them | |
WO1993022305A1 (en) | Tetronic, thiotetronic and tetramic acid derivatives as phospholipase a2 inhibitors | |
EP0114572A1 (en) | Substituted imidazo(1,5-a)pyridines | |
US4289707A (en) | Nitrogen heterocycles | |
US5705525A (en) | Thiophene compounds | |
US4596830A (en) | Novel derivatives of 2-(2-thienyl)-imidazo[4,5-b]-pyridines and their pharmaceutically acceptable salts | |
RU2068415C1 (en) | 5,7-dihydroxy-2-methyl-8-[4-(3-hydroxy-1)-(1-propyl)piperidinyl]-4h-1-benzopyran-4-one or its stereoisomers or pharmacologically acceptable acid-additive salts and a method of their synthesis | |
JP2796265B2 (en) | Aromatic compounds | |
US4910216A (en) | 2-(3,5-dimethyl-4-hydroxyphenyl)indole derivatives | |
KR830000450B1 (en) | Method for preparing phenyl alkanoic acid derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SCHERING AKTIENGESELLSCHAFT, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SKUBALLA, WERNER;BUCHMANN, BERND;REHWINKEL, HARTMUT;AND OTHERS;REEL/FRAME:009444/0604;SIGNING DATES FROM 19970930 TO 19971009 |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20030309 |